Optic nerve damage and regeneration failure are major features of trauma, glaucoma, and other blinding diseases. Developing strategies to promote anatomical regeneration and functional re-connection of injured optic nerve has been a long-standing challenge. We recently made a set of exciting discoveries showing that conditional deletion of PTEN (phosphatase and tensin homolog) or TSC1 (tuberous sclerosis 1) in adult retinal ganglion cells (RGCs) enabled robust long-distance axon regeneration after optic nerve injury (1), thereby establishing the first genetically defined mouse models with reproducible and robust optic nerve regeneration in the adult. The objectives of this proposed study are two-fold: to further explore the underlying mechanisms permitting axon regeneration in PTEN/TSC1 deleted neurons and to determine whether the regenerating axons could re-form synaptic connections and restore lost functions. We expect that the knowledge obtained from these studies can be translated into novel therapeutic strategies to promote functional recovery in patients with optic nerve injury, glaucoma and other types of eye diseases. PUBLIC HEALTH RELEVANCE: Our recent findings that PTEN or TSC1 knockout promotes robust optic nerve regeneration provide an unprecedented opportunity to study the cellular and molecular mechanisms enabling adult RGC axons to regenerate. Furthermore, the availability of these genetically defined models allows us, for the first time, to explore post-regeneration events such as axon pathfinding, targeting, synaptic reconnection and behavioral recovery in vivo. These studies should provide much needed insights into developing therapeutic strategies to promote axon regeneration and vision restoration after head trauma, glaucoma and other eye-related diseases.